PROJECT SUMMARY This project focuses on the identification of specific self-antigens that activate CD4+ T cells in systemic sclerosis. Cytotoxic CD4+T cells may directly contribute to cell death in tissues and secrete cytokines that lead to fibrosis. They likely receive help from activated B cells in tissues that in turn are induced by T follicular helper cells. Our goal is to use an unbiased approach to identify self antigens that activate clonally expanded cytotoxic CD4+T cells and/or T follicular helper cells from patients with diffuse systemic sclerosis who specifically have inherited HLA-DPB1*1301. Single cell cloning of CD4+ T cells will be used to identify matched T cell receptor alpha and beta chains from the most expanded cytotoxic CD4+ T cells and T follicular helper cells. Soluble T cell receptors will be generated. These soluble receptors will be used to screen a library of all human self peptides fused to HLA-DPB1*1301 and expressed in yeast.